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First Synthesis of 2′‐Deoxyfluoropuromycin Analogues: Experimental Insight into the Mechanism of the Staudinger Reaction
Author(s) -
Charafeddine Adib,
Dayoub Wissam,
Chapuis Hubert,
Strazewski Peter
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700058
Subject(s) - chemistry , azide , steric effects , epoxide , staudinger reaction , stereospecificity , sodium azide , medicinal chemistry , stereoselectivity , structural isomer , stereochemistry , coupling reaction , organic chemistry , catalysis
The N 6 , N 6 ‐dedimethyl‐2′‐deoxyfluoro analogue of puromycin (= 3′‐deoxy‐ N 6 , N 6 ‐dimethyl‐3′‐[ O ‐methyltyrosylamido]adenosine), its 2′,3′‐regioisomer and a 3′‐cytidyl‐5′‐(2′‐deoxyfluoro)puromycyl dinucleotide analogue were synthesized following an approach involving i) the diastereospecific nitrite‐assisted formation of a lyxo nucleosidic 2′,3′‐epoxide from an adenosine‐2′,3′‐ditriflate derivative in a biphasic solvent mixture; ii) the regio‐ and stereoselective epoxide ring opening with sodium azide under mildly acidic aqueous conditions, iii) the stereospecific introduction of the fluor atom using DAST and iv) the reaction between the nucleosidyl or dinucleotidyl azide and an active ester of the N‐protected amino acid using highly efficient solution conditions for the Staudinger–Vilarrasa coupling, to obtain the corresponding carboxamide directly from the in situ formed iminophosphorane. This coupling reaction furnished sterically quite demanding amides in 94 % isolated yields under very mild conditions and should therefore be of a more general value. Under certain reaction conditions we isolated (amino)acyltriazene derivatives from which dinitrogen was not eliminated. These secondary products are trapped and stabilized witnesses of the first intermediate of the Staudinger reaction, the phosphatriazenes (phosphazides, triazaphosphadienes) which usually eliminate dinitrogen in situ and rapidly rearrange into iminophosphoranes, unless they are derived from conjugated or sterically bulky azides and phosphines. The acyltriazenes could either be thermally decomposed or converted to the corresponding N ‐alkyl carboxamides through proton‐assisted elimination of dinitrogen. All compounds were carefully characterized through MS spectrometry, 1 H, 19 F, 31 P and 13 C NMR spectroscopy.